**8. The role of heat-shock proteins (HSP)**

Heat shock proteins (HSPs) were first discovered in 1962 as a group of highly conserved proteins that are induced by hyperthermia and other kinds of cellular insults.

There are four principal HSP: HSP-90, HSP-70, HSP-60 and the subgroup of small HSPs including HSP27.

Benign and malignant human prostatic cells respond to heat by increased expression of HSP *in vitro* and *in vivo.*

To obtain a more detailed insight on the effect of heat on prostatic cells, heat shock protein expression of normal and malignant prostatic cells has been studied.

Transrectal HIFU therapy induces intraprostatic necrosis surrounded by a zone characterized by a massive up-regulation of HSP expression.

Recently, several molecular heat shock proteins have been reported to be involved in development and progression of hormone-refractory prostate cancer.

HSP27 and HSP70 are the most strongly induced heat shock proteins during cellular stress (Fig. 9).

HSPs are not all of prognostic value, however some have been demonstrated to have clinical utility as prognostic markers: among this group of heat shock proteins, the most important one is HSP-27, which particularly plays a role in many immunological processes and might stimulate immune defence responses against tumour cells15.

Accumulating evidence suggests that HSP27 levels correlate with both hormone-refractory prostate cancer and development of resistance to heat. Nevertheless, the functional significance of changes in HSP27 expression associated with heat-resistant prostate cancer remains undefined.

High-Intensity Focused Ultrasound (HIFU)

modalities for localized prostate cancer.

anticolinergic treatment is required.

pharmacologically or surgically, if needed.

must be discussed with the patient before the treatment.

complication rate.

urinary tract.

prevention.

ultrasound.

outcome.

at the present time (Fig. 10).

therapies with each other, other therapies, or watchful waiting.

**10. Complications and side effects of HIFU treatment** 

complications but without affecting the oncologic outcome negatively.


There are no randomized controlled studies available to compare the outcome of these

The combination of a TURP performed just before an HIFU seems to reduce the

As of today, it is not possible to compare the outcome of HIFU with other treatment

HIFU is a minimally invasive treatment for prostate cancer, thus resulting in a low

Sometimes, minor complications can occour, in the vast majority of cases related to lower

The first one is urinary retention, commonly treated with longer catheterism. The most common is urge incontinence, due to the irritative effect of high-focused ultrasound on the bladder neck. Generally, it disappears in a couple of month, and only in rare cases

Lower urinary tract symptoms, such as frequency, nocturia, weak urinary stream, and so on, are prevented by Trans-Urethral Resection of Prostate (TUR-P), that is recommended to be done 6-8 weeks before HIFU treatment. Anyway, the surgeon is advised to administrate IPSS questionnaire (or equivalent) before the treatment end 3 months after the treatment, in order to assess persistent lower urinary tract symptoms, that should be treated

Infection is another possible complication of this treatment. Antibiotic prophylaxis should prevent this complication, if administrated in accordance with guidelines on infection

Among the major complications, the most important is recto-vesical or recto-urethral fistula. Only few cases are reported in literature. This complication can be initially treated with longer catheterization, but in some cases surgical repair is required. A common tip to avoid this complication is to safely set the target area on the ultrasound screen, as the slight wall of the rectum can easily lead to fistulization. Also, patients previously diagnosed with ulcerative recto-colitis must not be treated with high-intensity focused

The most important side-effect of HIFU treatment is erectile disfunction and impotency, due to the effect of high intensity ultrasound on the neural bundle. This effect is well known and

Color-doppler-combined technique is reported in literature in order to perform a sort of vessel-sparing procedure, thus resulting in a better outcome by the andrological point of view. However, there is not common agreement among the investigators about the effectiveness and the feasibility of this technique. For this reason, it cannot be recommended

The best management of the patient should include IIEF questionnaire (or equivalent) to be giver before the treatment and 6 months after the treatment in order to assess the sexual

Patients who are keen on having sexual activity should receive a proper treatment.

Fig. 9. HSP-70 expression in prostate tissue after HIFU treatment in a case of recurrence
